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Contains fulltext : 288354.pdf (Publisher’s version ) (Closed access) Introduction: Peritoneal carcinomatosis (PC) afflicts women with advanced gynecologic cancers. Patients with PC often require ostomies, gastric tubes, or catheters to palliate symptoms, yet patients and caregivers report feeling unprepared to manage these devices. The purpose of this study was to develop and field test the Building Out Lifelines for Safety, Trust, Empowerment, and Renewal (BOLSTER) intervention to support patients and their caregivers after hospitalization for PC. Materials and Methods: We adapted components of the Standard Nursing Intervention Protocol with stakeholders and topical experts. We developed educational content; built a smartphone application to assess patients' symptoms; and assessed preliminary feasibility and acceptability in two single-arm prepilot studies. Eligible participants were English-speaking adults hospitalized for gynecologic cancer-associated PC and their caregivers. Feasibility criteria were a ≥50% consent-to-approach ratio and ≥80% outcome measure completion. The acceptability criterion was ≥70% of participants recommending BOLSTER. Results: During the first prepilot, BOLSTER was a 10-week intervention. While 7/8 (87.5%) approached patients consented, we experienced high attrition to hospice. Less than half of patients (3/7) and caregivers (3/7) completed outcome measures. For the second prepilot, BOLSTER was a four-week intervention. All (7/7) approached patients consented. Two withdrew before participating in any study activity because they were "too overwhelmed." We excluded data from one caregiver who completed baseline measures with the patient's assistance. All remaining patients (5/5) and caregivers (4/4) completed outcome measures and recommended BOLSTER. Conclusion: BOLSTER is a technology-enhanced, nurse-led intervention that is feasible and acceptable to patients with gynecologic cancer-associated PC and their caregivers.

The coronavirus (COVID-19) pandemic has brought focus to the effects of anxiety on children. This study aimed to review the existing literature regarding the impact of the pandemic on pediatric anxiety. This review analyzed the existing literature between the open-sourced collection on PubMed inputting “anxiety disorder in children during pandemic” and “pediatric anxiety OR child anxiety AND COVID” and that of the Journal of the American Academy of Child & Adolescent Psychiatry using the keywords “social anxiety AND COVID.” This yielded 149 + 312 (461) entries and 68 articles were selected. Anxiety was found to have a prevalence of 18.9–23.87% in children during the COVID-19 pandemic whereas adolescent populations demonstrated a prevalence of 15.4–39.9%. Female gender was the most studied risk factor and physical activity was the most documented preventative factor. This review supported the notion that the COVID-19 pandemic is a major contributor to anxiety in the pediatric population.

Background Despite interest among North American orthopaedic residents to pursue rotations in resource-limited settings, little is known regarding resident motivations and impact on host surgeons. Methods Surveys were distributed to North American orthopaedic surgeons and trainees who participated in international rotations during residency to assess motivations for participation and to orthopaedic surgeons at partnering low- and middle-income country (LMIC) institutions to assess impact of visiting trainees. Results Responses were received from 136 North American resident rotators and 51 LMIC host surgeons and trainees. North American respondents were motivated by a desire to increase surgical capacity at the LMIC while host surgeons reported a greater impact from learning from residents than on surgical capacity. Negative aspects reported by hosts included selfishness, lack of reciprocity, racial discrimination, competition for surgical experience, and resource burdens. Conclusions The motivations and impact of orthopaedic resident rotations in LMICs need to be aligned. Host perceptions and bidirectional educational exchange should be incorporated into partnership guidelines.

Background Ketamine as an antidepressant improves anhedonia as early as 2 hours after infusion. These drug effects are thought to be exerted via actions on reward-related brain areas—yet these actions remain largely unknown. Our study investigates ketamine’s effects during the anticipation and receipt of an expected reward, after the psychotomimetic effects of ketamine have passed, when early antidepressant effects are reported. Methods We examined ketamine’s effects during the anticipation and receipt of expected rewards on predefined brain areas, namely, the dorsal and ventral striatum, ventral tegmental area, amygdala, and insula. We recruited 37 male and female participants with remitted depression who were free from symptoms and antidepressant treatments at the time of the scan. Participants were scanned 2 hours after drug administration in a double-blind crossover design (ketamine: 0.5 mg/kg and placebo) while performing a monetary reward task. Results A significant main effect of ketamine was observed across all regions of interest during the anticipation and feedback phases of win and no-win trials. The drug effects were particularly prominent in the nucleus accumbens and putamen, which showed increased activation on the receipt of smaller rewards compared with neutral. The levels of (2R,6R)-hydroxynorketamine 2 hours after infusion significantly correlated with the activation observed in the ventral tegmental area for that contrast. Conclusions These findings demonstrate that ketamine can produce detectable changes in reward-related brain areas 2 hours after infusion, which occur without symptom changes and support the idea that ketamine might improve reward-related symptoms via modulation of response to feedback.

To better understand the potential risks of Nipah virus emergence in Cambodia by studying different components of the interface between humans and bats.From 2012 to 2016, we conducted a study at two sites in Kandal and Battambang provinces where fruit bats (Our results confirmed circulation of Nipah virus in fruit bats (28 of 3930 urine samples positive by polymerase chain reaction testing). We identified clear potential routes for virus transmission to humans through local practices, including fruit consumed by bats and harvested by humans when Nipah virus is circulating, and palm juice production. Nevertheless, in the serological survey of 418 potentially exposed people, none of them were seropositive to Nipah virus. Differences in agricultural practices among the regions where Nipah virus has emerged may explain the situation in Cambodia and point to actions to limit the risks of virus transmission to humans.Human practices are key to understanding transmission risks associated with emerging infectious diseases. Social science disciplines such as anthropology need to be integrated in health programmes targeting emerging infectious diseases. As bats are hosts of major zoonotic pathogens, such integrated studies would likely also help to reduce the risk of emergence of other bat-borne diseases.Mieux comprendre les risques potentiels d'émergence du virus Nipah au Cambodge en étudiant différents composants de l'interface entre humains et chauves-souris.De 2012 à 2016, nous avons réalisé une étude à deux endroits dans les provinces de Kandal et Battambang, où nichent les chauves-souris frugivores (Nos résultats ont confirmé la circulation du virus Nipah chez les chauves-souris frugivores (28 échantillons d'urine sur 3930 se sont révélés positifs lors des tests de réaction en chaîne par polymérase). Nous avons clairement identifié plusieurs vecteurs de transmission potentiels aux humains liés aux pratiques locales, dont les fruits consommés par les chauves-souris et récoltés par les humains lorsque le virus Nipah circule, ainsi que la production de jus de palme. Néanmoins, une enquête sérologique menée auprès de 418 personnes potentiellement exposées a montré qu'aucune d'entre elles n'était séropositive au virus Nipah. Les différences au niveau des pratiques agricoles dans les régions où le virus Nipah est apparu pourrait expliquer la situation au Cambodge, et conduire à des actions qui permettront de limiter les risques de transmission du virus aux humains.Les pratiques humaines sont la clé d'une meilleure compréhension des risques de transmission associés aux maladies infectieuses émergentes. Certaines disciplines de sciences sociales telles que l'anthropologie doivent être intégrées dans les programmes de santé qui ciblent les maladies infectieuses émergentes. Étant donné que les chauves-souris sont porteuses d'agents pathogènes zoonotiques majeurs, des études intégrées de ce type pourraient contribuer à réduire le risque d'émergence d'autres maladies propagées par les chauves-souris.Entender mejor los riesgos potenciales de la aparición del virus Nipah en Camboya mediante el estudio de los diversos componentes de la interfaz entre los seres humanos y los murciélagos.De 2012 a 2016, se realizó un estudio en dos lugares de las provincias de Kandal y Battambang en donde habitan los murciélagos fruteros (Los resultados confirmaron la circulación del virus Nipah en murciélagos fruteros (28 de 3930 muestras de orina positivas en la prueba de reacción en cadena de la polimerasa). Se identificaron las rutas claras de transmisión del virus a los seres humanos a través de las prácticas locales, incluidas las frutas que consumen los murciélagos y que los seres humanos recolectan cuando el virus Nipah está en circulación, y la producción de zumo de palma. Sin embargo, según el estudio serológico de 418 personas potencialmente expuestas, ninguna de ellas fue seropositiva al virus Nipah. Es posible que las diferencias en las prácticas agrícolas entre las regiones en donde el virus Nipah se ha presentado expliquen la situación en Camboya y señalen las medidas para limitar los riesgos de transmisión del virus a los seres humanos.Las prácticas de los seres humanos son esenciales para entender los riesgos de transmisión asociados a las enfermedades infecciosas emergentes. Las disciplinas de las ciencias sociales, como la antropología, se deben integrar en los programas de salud que se ocupan de esas enfermedades. Teniendo en cuenta que los murciélagos son huéspedes de los principales patógenos zoonóticos, es probable que esos estudios integrados también ayuden a reducir el riesgo de aparición de otras enfermedades que se transmiten por los murciélagos.الغرض تحقيق فهم أفضل للمخاطر المحتملة لظهور فيروس نيباه في كمبوديا عن طريق دراسة المكونات المختلفة للتفاعل بين البشر والخفافيش. الطريقة من عام 2012 حتى عام 2016، قمنا بإجراء دراسة في موقعين في مقاطعتي كاندال وباتامبانج حيث تستوطن خفافيش الفاكهة (旨在通过研究人与蝙蝠之间相互接触的不同部分，更好地了解柬埔寨境内的尼帕病毒潜在风险。.从 2012 年至 2016 年，我们在坎达尔和马德望省的两个地点进行了研究，这些地方都栖息着果蝠（我们的结果证实了尼帕病毒在果蝠中的传播（通过聚合酶链反应测试发现 3930 个尿液样本中有 28 个呈阳性）。我们通过当地实践确定了将病毒传播给人类的明确潜在途径，包括传播尼帕病毒时蝙蝠食用的和人类收获的果实，以及棕榈汁的生产。尽管如此，在对 418 名潜在接触者进行的血清学调查中，没有人对尼帕病毒呈血清反应阳性。已经出现尼帕病毒的地区中在农业实践方面的差异可能说明了柬埔寨的情况以及限制病毒传播给人类的风险的行动指向。.人类实践是了解与新发传染病相关的传播风险的关键。需要将人类学等社会科学学科纳入针对新发传染病的卫生方案。由于蝙蝠是主要的人畜共患病病原体的宿主，因此此类综合研究还可能有助于降低其他蝙蝠传播疾病出现的风险。.Добиться лучшего понимания потенциальных рисков появления вируса Нипах в Камбодже за счет изучения разного рода компонентов взаимодействия людей и летучих мышей.В период с 2012 по 2016 год авторы провели исследование в двух районах провинций Кандаль и Баттамбанг со значительными колониями крыланов (Было подтверждено, что в организмах крыланов циркулирует вирус Нипах (28 из 3930 образцов мочи были положительными по результатам тестирования методом полимеразной цепной реакции). Авторы выявили четкие потенциальные пути передачи вируса людям через принятые в этих местностях практикуемые виды деятельности, включая сбор людьми фруктов, которыми питаются крыланы, во время циркуляции вируса Нипах и добычу пальмового сока. Тем не менее в серологическом исследовании 418 потенциально зараженных людей ни один человек не продемонстрировал положительного результата при серологической диагностике вируса Нипах. Различия в сельскохозяйственных практиках, существующие между регионами Камбоджи, где отмечается появление вируса Нипах, могут объяснять сложившуюся ситуацию и указывать на необходимые мероприятия с целью ограничения риска передачи вируса людям.Практикуемые людьми виды деятельности являются ключом к пониманию рисков, связанных с передачей новых инфекционных заболеваний. Социальные научные дисциплины, такие как антропология, должны быть включены в программы медицинского обслуживания, направленные на борьбу с новыми инфекционными заболеваниями. Поскольку летучие мыши являются переносчиками серьезных зоонозных патогенов, такие объединенные исследования могут способствовать снижению риска появления других заболеваний, передающихся через летучих мышей.

Background The intestinal microbiota play a key role in the onset, progression, and recurrence of Crohn disease (CD). Most microbiome studies assay fecal material, which does not provide region-specific information on mucosally adherent bacteria that directly interact with host systems. Changes in luminal oxygen have been proposed as a contributor to CD dybiosis. Methods The authors generated 16S rRNA data using colonic and ileal mucosal bacteria from patients with CD and without inflammatory bowel disease. We developed profiles reflecting bacterial abundance within defined aerotolerance categories. Bacterial diversity, composition, and aerotolerance profiles were compared across intestinal regions and disease phenotypes. Results Bacterial diversity decreased in CD in both the ileum and the colon. Aerotolerance profiles significantly differed between intestinal segments in patients without inflammatory bowel disease, although both were dominated by obligate anaerobes, as expected. In CD, high relative levels of obligate anaerobes were maintained in the colon and increased in the ileum. Relative abundances of similar and distinct taxa were altered in colon and ileum. Notably, several obligate anaerobes, such as Bacteroides fragilis, dramatically increased in CD in one or both intestinal segments, although specific increasing taxa varied across patients. Increased abundance of taxa from the Proteobacteria phylum was found only in the ileum. Bacterial diversity was significantly reduced in resected tissues of patients who developed postoperative disease recurrence across 2 independent cohorts, with common lower abundance of bacteria from the Bacteroides, Streptococcus, and Blautia genera. Conclusions Mucosally adherent bacteria in the colon and ileum show distinct alterations in CD that provide additional insights not revealed in fecal material.

BackgroundAt ketamine and esketamine doses at which antidepressant doses are achieved, these agents are relatively selective, noncompetitive, N-methyl-D-aspartate receptor antagonists. However, at substantially higher doses, ketamine has shown mu-opioid receptor (MOR–gene symbol: OPRM1) agonist effects. Preliminary clinical studies showed conflicting results on whether naltrexone, a MOR antagonist, blocks the antidepressant action of ketamine. We examined drug-induced or endogenous MOR involvement in the antidepressant and dissociative responses to esketamine by assessing the effects of a functional single nucleotide polymorphism rs1799971 (A118G) of OPRM1, which is known to alter MOR agonist-mediated responses.MethodsParticipants with treatment-resistant depression from 2 phase III, double-blind, controlled trials of esketamine (or placebo) nasal spray plus an oral antidepressant were genotyped for rs1799971. Participants received the experimental agents twice weekly for 4 weeks. Antidepressant responses were rated using the change in Montgomery–Åsberg Depression Rating Scale (MADRS) score on days 2 and 28 post-dose initiation, and dissociative side effects were assessed using the Clinician-Administered Dissociative-States Scale at 40 minutes post-dose on days 1 and 25.ResultsIn the esketamine + antidepressant arm, no significant genotype effect of single nucleotide polymorphism rs1799971 (A118G) on MADRS score reductions was detected on either day 2 or 28. By contrast, in the antidepressant + placebo arm, there was a significant genotype effect on MADRS score reductions on day 2 and a nonsignificant trend on day 28 towards an improvement in depression symptoms in G-allele carriers. No significant genotype effects on dissociative responses were detected.ConclusionsVariation in rs1799971 (A118G) did not affect the antidepressant response to esketamine + antidepressant. Antidepressant response to antidepressant + placebo was increased in G-allele carriers, compatible with previous reports that release of endorphins/enkephalins may play a role in mediating placebo effect.Trial RegistrationNCT02417064 and NCT02418585; www.clinicaltrials.gov

Background & Aims Intestinal epithelial cell (IEC) barrier dysfunction is critical to the development of Crohn’s disease (CD). However, the mechanism is understudied. We recently reported increased microRNA-31-5p (miR-31-5p) expression in colonic IECs of CD patients, but downstream targets and functional consequences are unknown. Methods microRNA-31-5p target genes were identified by integrative analysis of RNA- and small RNA-sequencing data from colonic mucosa and confirmed by quantitative polymerase chain reaction in colonic IECs. Functional characterization of activin receptor-like kinase 1 (ACVRL1 or ALK1) in IECs was performed ex vivo using 2-dimensional cultured human primary colonic IECs. The impact of altered colonic ALK1 signaling in CD for the risk of surgery and endoscopic relapse was evaluated by a multivariate regression analysis and a Kaplan–Meier estimator. Results ALK1 was identified as a target of miR-31-5p in colonic IECs of CD patients and confirmed using a 3’-untranslated region reporter assay. Activation of ALK1 restricted the proliferation of colonic IECs in a 5-ethynyl-2-deoxyuridine proliferation assay and down-regulated the expression of stemness-related genes. Activated ALK1 signaling increased colonic IEC differentiation toward colonocytes. Down-regulated ALK1 signaling was associated with increased stemness and decreased colonocyte-specific marker expression in colonic IECs of CD patients compared with healthy controls. Activation of ALK1 enhanced epithelial barrier integrity in a transepithelial electrical resistance permeability assay. Lower colonic ALK1 expression was identified as an independent risk factor for surgery and was associated with a higher risk of endoscopic relapse in CD patients. Conclusions Decreased colonic ALK1 disrupted colonic IEC barrier integrity and was associated with poor clinical outcomes in CD patients., Graphical abstract

SUMMARY End-binding proteins (EBs) are widely viewed as master regulators of microtubule dynamics and function. Here, we show that while EB1 mediates the dynamic microtubule capture of herpes simplex virus type 1 (HSV-1) in fibroblasts, in neuronal cells, infection occurs independently of EBs through stable microtubules. Prompted by this, we find that transforming acid coiled-coil protein 3 (TACC3), widely studied in mitotic spindle formation, regulates the cytoplasmic localization of the microtubule polymerizing factor chTOG and influences microtubule plus-end dynamics during interphase to control infection in distinct cell types. Furthermore, perturbing TACC3 function in neuronal cells resulted in the formation of disorganized stable, detyrosinated microtubule networks and changes in cellular morphology, as well as impaired trafficking of both HSV-1 and transferrin. These trafficking defects in TACC3-depleted cells were reversed by the depletion of kinesin-1 heavy chains. As such, TACC3 is a critical regulator of interphase microtubule dynamics and stability that influences kinesin-1-based cargo trafficking., In Brief While EB proteins are widely studied as master regulators of microtubule plus-end dynamics, Furey et al. report EB-independent regulation of microtubule arrays and cargo trafficking by the transforming acid coiled-coil-containing protein, TACC3. By controlling the formation of detyrosinated stable microtubule networks, TACC3 influences kinesin-1-based sorting of both host and pathogenic cargoes., Graphical Abstract

Acute ozone (O3) exposure is associated with multiple adverse cardiorespiratory outcomes, the severity of which varies across individuals in human populations and inbred mouse strains. However, molecular determinants of response, including susceptibility biomarkers that distinguish who will develop severe injury and inflammation, are not well characterized. We and others have demonstrated that airway macrophages (AMs) are an important resident immune cell type that are functionally and transcriptionally responsive to O3 inhalation. Here, we sought to explore influences of strain, exposure, and strain-by-O3 exposure interactions on AM gene expression and identify transcriptional correlates of O3-induced inflammation and injury across six mouse strains, including five Collaborative Cross (CC) strains. We exposed adult mice of both sexes to filtered air (FA) or 2 ppm O3 for 3 h and measured inflammatory and injury parameters 21 h later. Mice exposed to O3 developed airway neutrophilia and lung injury with strain-dependent severity. In AMs, we identified a common core O3 transcriptional response signature across all strains, as well as a set of genes exhibiting strain-by-O3 exposure interactions. In particular, a prominent gene expression contrast emerged between a low- (CC017/Unc) and high-responding (CC003/Unc) strain, as reflected by cellular inflammation and injury. Further inspection indicated that differences in their baseline gene expression and chromatin accessibility profiles likely contribute to their divergent post-O3 exposure transcriptional responses. Together, these results suggest that aspects of O3-induced respiratory responses are mediated through altered AM transcriptional signatures and further confirm the importance of gene-environment interactions in mediating differential responsiveness to environmental agents.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to similar to 22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.

Background Despite widespread recommendations to favor lipase over amylase in the diagnosis and management of acute pancreatitis, many routine hospital laboratories still offer amylase testing. This study sought to evaluate and compare ordering patterns of amylase and lipase in patients with acute pancreatitis. Methods We analyzed 438 patients with acute pancreatitis admitted to our hospital. Data collection included pancreatitis etiology and management as well as biochemical profiles of amylase and lipase. We compared serial ordering patterns, degree of biomarker elevation, and normalization kinetics. Results All patients had at least one lipase ordered during their admission, and only 51 patients (12%) had at least one amylase ordered. On average, lipase was elevated 5 times higher above its respective upper reference limit than amylase at admission. Pancreatitis etiology was skewed toward gallstones in the amylase group as compared to the lipase only group (69% vs. 43%), and surgical patients (laparoscopic cholecystectomy) were more likely to have amylase ordered and/or trended. Conclusions Amylase measurement was not necessary in the diagnosis and management of 88% of patients with acute pancreatitis. Of patients for whom amylase was ordered, it was common for these patients to be those referred to surgical procedures, possibly because amylase normalization may be documented faster than that of lipase.

Summary Background Well designed, large comparative effectiveness trials assessing the efficacy of primary interventions for faecal incontinence are few in number. The objectives of this study were to compare different combinations of anorectal manometry-assisted biofeedback, loperamide, education, and oral placebo. Methods In this randomised factorial trial, participants were recruited from eight clinical sites in the USA. Women with at least one episode of faecal incontinence per month in the past 3 months were randomly assigned 0·5:1:1:1 to one of four groups: oral placebo plus education only, placebo plus anorectal manometry-assisted biofeedback, loperamide plus education only, and loperamide plus anorectal manometry-assisted biofeedback. Participants received 2 mg per day of loperamide or oral placebo with the option of dose escalation or reduction. Women assigned to biofeedback received six visits, including strength and sensory biofeedback training. All participants received a standardised faecal incontinence patient education pamphlet and were followed for 24 weeks after starting treatment. The primary endpoint was change in St Mark's (Vaizey) faecal incontinence severity score between baseline and 24 weeks, analysed by intention-to-treat using general linear mixed modelling. Investigators, interviewers, and outcome evaluators were masked to biofeedback assignment. Participants and all study staff other than the research pharmacist were masked to medication assignment. Randomisation took place within the electronic data capture system, was stratified by site using randomly permuted blocks (block size 7), and the sizes of the blocks and the allocation sequence were known only to the data coordinating centre. This trial is registered with ClinicalTrials.gov, number NCT02008565. Findings Between April 1, 2014, and Sept 30, 2015, 377 women were enrolled, of whom 300 were randomly assigned to placebo plus education (n=42), placebo plus biofeedback (n=84), loperamide plus education (n=88), and the combined intervention of loperamide plus biofeedback (n=86). At 24 weeks, there were no differences between loperamide versus placebo (model estimated score change −1·5 points, 95% CI −3·4 to 0·4, p=0·12), biofeedback versus education (−0·7 points, −2·6 to 1·2, p=0·47), and loperamide and biofeedback versus placebo and biofeedback (−1·9 points, −4·1 to 0·3, p=0·092) or versus loperamide plus education (−1·1 points, −3·4 to 1·1, p=0·33). Constipation was the most common grade 3 or higher adverse event and was reported by two (2%) of 86 participants in the loperamide and biofeedback group and two (2%) of 88 in the loperamide plus education group. The percentage of participants with any serious adverse events did not differ between the treatment groups. Only one serious adverse event was considered related to treatment (small bowel obstruction in the placebo and biofeedback group). Interpretation In women with normal stool consistency and faecal incontinence bothersome enough to seek treatment, we were unable to find evidence against the null hypotheses that loperamide is equivalent to placebo, that anal exercises with biofeedback is equivalent to an educational pamphlet, and that loperamide and biofeedback are equivalent to oral placebo and biofeedback or loperamide plus an educational pamphlet. Because these are common first-line treatments for faecal incontinence, clinicians could consider combining loperamide, anal manometry-assisted biofeedback, and a standard educational pamphlet, but this is likely to result in only negligible improvement over individual therapies and patients should be counselled regarding possible constipation. Funding Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institutes of Health Office of Research on Women's Health

Background In the search for novel treatments for depression, ketamine has emerged as a unique agent with rapid antidepressant effects. Experimental tasks involving emotional processing can be used during functional magnetic resonance imaging scanning to investigate ketamine’s effects on brain function in major depressive disorder (MDD). This study examined ketamine’s effects on functional magnetic resonance imaging activity during an emotional processing task. Methods A total of 33 individuals with treatment-resistant MDD and 24 healthy control participants (HCs) took part in this double-blind, placebo-controlled crossover study. Participants received ketamine and placebo infusions 2 weeks apart, and functional magnetic resonance imaging scans were conducted at baseline and 2 days after each infusion. Blood oxygen level–dependent signal was measured during an emotional processing task, and a linear mixed-effects model was used to analyze differences in activation among group, drug, and task-specific factors. Results A group-by-drug interaction was observed in several brain regions, including a right frontal cluster extending into the anterior cingulate cortex and insula. Participants with MDD had greater activity than HCs after placebo infusion but showed lower activity after ketamine infusion, which was similar to the activity in HCs after placebo. A group-by-drug-by-task condition interaction was also found, which showed further differences that varied between implicit and explicit emotional conditions. Conclusions The main results indicate that ketamine had differential effects on brain activity in participants with MDD versus HCs. The pattern of activation in participants with MDD after ketamine infusion resembled the activation in HCs after placebo infusion, suggesting a normalization of function during emotional processing. The findings contribute to a better understanding of ketamine’s actions in the brain.

Background and AimsThe host receptor for SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2), is highly expressed in small intestine. Our aim was to study colonic ACE2 expression in Crohn’s disease (CD) and non-inflammatory bowel disease (non-IBD) controls. We hypothesized that the colonic expression levels of ACE2 impacts CD course.MethodsWe examined the expression of colon ACE2 using RNA-seq and quantitative (q) RT-PCR from 69 adult CD and 14 NIBD control patients. In a subset of this cohort we validated ACE2 protein expression and localization in formalin-fixed, paraffin-embedded matched colon and ileal tissues using immunohistochemistry. The impact of increased ACE2 expression in CD for the risk of surgery was evaluated by a multivariate regression analysis and a Kaplan-Meier estimator. To provide critical support for the generality of our findings, we analyzed previously published RNA-seq data from two large independent cohorts of CD patients.ResultsColonic ACE2 expression was significantly higher in a subset of adult CD patients (ACE2-high CD). IHC in a sampling of ACE2-high CD patients confirmed high ACE2 protein expression in the colon and ileum compared to ACE2-low CD and NIBD patients. Notably, we found that ACE2-high CD patients are significantly more likely to undergo surgery within 5 years of diagnosis, with a Cox regression analysis finding that high ACE2 levels is an independent risk factor (OR 2.18; 95%CI, 1.05-4.55; p=0.037).ConclusionIncreased intestinal expression of ACE2 is associated with deteriorated clinical outcomes in CD patients. These data point to the need for molecular stratification that may impact CD disease-related outcomes.

Background & Aims The prevalence and significance of digestive manifestations in coronavirus disease 2019 (COVID-19) remain uncertain. We aimed to assess the prevalence, spectrum, severity, and significance of digestive manifestations in patients hospitalized with COVID-19. Methods Consecutive patients hospitalized with COVID-19 were identified across a geographically diverse alliance of medical centers in North America. Data pertaining to baseline characteristics, symptomatology, laboratory assessment, imaging, and endoscopic findings from the time of symptom onset until discharge or death were abstracted manually from electronic health records to characterize the prevalence, spectrum, and severity of digestive manifestations. Regression analyses were performed to evaluate the association between digestive manifestations and severe outcomes related to COVID-19. Results A total of 1992 patients across 36 centers met eligibility criteria and were included. Overall, 53% of patients experienced at least 1 gastrointestinal symptom at any time during their illness, most commonly diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%). In 74% of cases, gastrointestinal symptoms were judged to be mild. In total, 35% of patients developed an abnormal alanine aminotransferase or total bilirubin level; these were increased to less than 5 times the upper limit of normal in 77% of cases. After adjusting for potential confounders, the presence of gastrointestinal symptoms at any time (odds ratio, 0.93; 95% CI, 0.76–1.15) or liver test abnormalities on admission (odds ratio, 1.31; 95% CI, 0.80–2.12) were not associated independently with mechanical ventilation or death. Conclusions Among patients hospitalized with COVID-19, gastrointestinal symptoms and liver test abnormalities were common, but the majority were mild and their presence was not associated with a more severe clinical course.

Background While total joint replacement (TJR) is the most effective treatment for end-stage osteoarthritis (OA), one-third of patients do not experience clinically important improvement in pain or function following the surgery. Thus, it is important to identify factors for nonresponders and develop strategies to improve TJR outcomes. Methods Study participants were patients who underwent TJR (hip/knee) due to OA and completed the WOMAC before and on average 4 years after surgery. Nonresponders (pain nonresponders, function nonresponders, pain and function nonresponders) were determined using the WOMAC change score from baseline to follow-up under two previously reported criteria. Eighty-eight self-reported factors collected by a general health questionnaire were examined for associations with nonresponders. Results A total of 601 patients (30.8% hip and 69.2% knee replacement) were included; 18% of them were found to be either pain or function nonresponders. Nine factors were identified in the univariable analyses to be associated with nonresponders, and 5 of them (clinical depression, multisite musculoskeletal pain [MSMP], younger age, golfer’s elbow, and driving more than 4 hours on average per working day) remained significant in the multivariable analyses in at least one of six categories. Clinical depression, having MSMP, and younger age were the major factors to be independently associated with nonresponders across five categories. In addition, two factors (age at menopause and age at hysterectomy) were significantly associated with female nonresponders. Conclusion Our data suggested potential roles of pain perception, widespread pain sensitization, patient expectations, and early menopause in females in TJR outcomes, warranting further investigation.

Objective To identify endotypes of osteoarthritis (OA) by a metabolomics analysis. Methods Study participants included hip/knee OA patients and controls. Fasting plasma samples were metabolomically profiled. Common factor analysis and K-means clustering were applied to the metabolomics data to identify the endotypes of OA patients. Logistic regression was utilized to identify the most significant metabolites contributing to the endotypes. Clinical and epidemiological factors were examined in relation to the identified OA endotypes. Results Six hundred and fifteen primary OA patients and 237 controls were included. Among the 186 metabolites measured, 162 passed the quality control analysis. The 615 OA patients were classified in three clusters (A, 66; B, 200; and C, 349). Patients in cluster A had a significantly higher concentration of butyrylcarnitine (C4) than other clusters and controls (all P Conclusion Our data suggest three possible clinically actionable endotypes in primary OA: muscle weakness, arginine deficit and low inflammatory OA.

Background This randomized, placebo-controlled, crossover trial examined the antidepressant efficacy of the muscarinic antagonist scopolamine in major depressive disorder subjects with more severe and refractory forms of major depressive disorder relative to previous reports. Methods Participants included 23 medication-free major depressive disorder subjects (12 F/11 M, 20–55 years) currently experiencing a major depressive episode. Subjects had scored ≥20 on the Montgomery-Asberg Depression Rating Scale. Following a single-blind, placebo lead-in, participants were randomized to receive 2 counterbalanced blocks of 3 i.v. infusions of scopolamine (4 μg/kg) and placebo in a double-blind manner. The primary and secondary outcomes were the Montgomery-Asberg Depression Rating Scale and the Hamilton Anxiety Rating Scale, respectively. Magnetoencephalography and plasma brain-derived neurotrophic factor concentrations were obtained prior to and after each treatment phase. Results As assessed by both the Montgomery-Asberg Depression Rating Scale and Hamilton Anxiety Rating Scale, scopolamine had no significant antidepressant or anxiolytic effects relative to placebo. No significant drug vs placebo effects were seen in magnetoencephalography gamma power or brain-derived neurotrophic factor plasma concentrations, and brain-derived neurotrophic factor changes did not correlate with change in Montgomery-Asberg Depression Rating Scale score in response to scopolamine. Conclusions These results do not support the efficacy of scopolamine for more severe or refractory forms of depression. No pre- to post-infusion changes in plasma brain-derived neurotrophic factor were detected, and magnetoencephalography gamma power changed only in the placebo lead-in, suggesting that these biomarker measures were not affected by scopolamine in this cohort. While difficult to interpret given the lack of antidepressant response, the findings suggest that the neurobiological effects of ketamine and scopolamine are at least partly distinct.

Objective Trauma resuscitation protocols have unified the care of trauma patients and significantly improved outcomes. However, the success of the Advanced Trauma Life Support course is difficult to reproduce in developing countries due to set-up costs, limitations of resources, and variations of practice. The objective of this study is to assess the Trauma Evaluation and Management (TEAM) course as a low-cost alternative for trauma resuscitation teaching in Low and Middle Income Countries (LMIC). Design As part of the Team Broken Earth initiative, TEAM course was provided to the health care professionals in Haiti. At its conclusion, participants were asked to complete a survey evaluating the course. Qualitative and quantitative data were analyzed to evaluate the perception of the course. Setting The course was provided in Port-au-Prince, Haiti. Participants A total of 80 health care professionals participated in the course. Response was obtained from 69 participants, which comprised of 32 physicians, 10 Emergency Medical Technicians (EMT), 22 nurses, and 5 medical trainees. Results The course was well received by physicians, nurses, and EMT with an average score of 90.6%. Question analysis revealed a lower satisfaction of physicians for the course manual and teaching materials, and information related to decisions for transfer of patients. EMT consistently felt that the course was not tailored to their learning and practice needs. Written feedback demonstrated several areas of weaknesses including need for improvements in translations, hands-on practice, and educational materials. Conclusions Overall, the TEAM course was well received. Analysis demonstrated a need for adjustments specific to LMIC including a focus on prehospital assessment, increased nursing responsibilities, and unavailability of specialist’s referrals. Team Broken Earth intends to take these findings into consideration and continue to provide the TEAM course to other LMIC.

The reported proof of principle study demonstrated the feasibility of local delivery of a c-Met inhibitor (VXc-140) in a subcutaneous xenograft tumor model. VXc-140 was formulated in a wafer delivery system for direct implantation into the tumor. Systemic and local tumor exposure of VXc-140 was analyzed. High tumor exposures coupled with fast release of compound were associated with significant tumor regression and reduction in tumor levels of phosphorylated c-Met. High VXc-140 tumor-to-plasma ratios (∼42 at the tumor periphery) were achieved. The tumor response achieved (7/11 partial response) with VXc-140 with the local delivery in the wafer (4 mg over 15 days) was comparable to the regression observed (11/15 partial response) for VXc-140 in the oral delivery (∼8 mg total administered once a day for 2 weeks). Notably, the plasma levels in animals implanted with VXc-140 wafers ranged from 2 to 4 μM, which, although higher than trough levels achieved with oral administration, were well below oral Cmax levels (∼42 μM) suggesting that toxicities associated with Cmax exposure may be reduced or eliminated by local delivery. The high tumor to plasma exposure of VXc-140 and the efficacy observed with local wafer delivery warrants further exploration into the utility of local delivery.

Background An urgent need exists for faster-acting pharmacological treatments in major depressive disorder (MDD). The glutamatergic modulator ketamine has been shown to have rapid antidepressant effects, but much remains unknown about its mechanism of action. Functional MRI (fMRI) can be used to investigate how ketamine impacts brain activity during cognitive and emotional processing. Methods This double-blind, placebo-controlled, crossover study of 33 unmedicated participants with MDD and 26 healthy controls (HCs) examined how ketamine affected fMRI activation during an attentional bias dot probe task with emotional face stimuli across multiple time points. A whole brain analysis was conducted to find regions with differential activation associated with group, drug session, or dot probe task-specific factors (emotional valence and congruency of stimuli). Results A drug session by group interaction was observed in several brain regions, such that ketamine had opposite effects on brain activation in MDD versus HC participants. Additionally, there was a similar finding related to emotional valence (a drug session by group by emotion interaction) in a large cluster in the anterior cingulate and medial frontal cortex. Conclusions The findings show a pattern of brain activity in MDD participants following ketamine infusion that is similar to activity observed in HCs after placebo. This suggests that ketamine may act as an antidepressant by normalizing brain function during emotionally valenced attentional processing. Clinical trial NCT#00088699: https://www.clinicaltrials.gov/ct2/show/NCT00088699, Highlights • The effects of ketamine versus placebo on brain activation were studied using fMRI. • MDD and healthy participants were tested on an fMRI emotion-based attentional task. • Ketamine had opposite effects on brain activity in MDD versus healthy participants. • In MDD, brain activity post-ketamine was similar to healthy controls post-placebo. • These findings suggest that ketamine may act by normalizing brain function.

OBJECTIVE: To evaluate the effects of early treatment with CPAP on nutritional intake and in-hospital growth rates of extremely preterm (EPT) infants. STUDY DESIGN: EPT infants (24–0/7 to 27–6/7 weeks of gestation) enrolled in the Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) were included. EPT infants who died before 36 weeks’ postmenstrual age (PMA) were excluded. The growth rates from birth to 36 weeks’ PMA and follow-up outcomes at 18–22 months’ corrected age of EPT infants randomized at birth to either early CPAP (intervention group) or early intubation for surfactant administration (control group) were analyzed. RESULTS: 810 of 1316 infants enrolled in SUPPORT (414 in intervention group, 396 in control group) had growth data analyzed. Median gestational age was 26 weeks and mean birthweight was 839 grams. Baseline characteristics, total nutritional intake, and in-hospital comorbidities were not significantly different between groups. In a regression model, growth rates between birth and 36 weeks’ PMA as well as growth rates during multiple intervals from birth to day 7, day 7 to14, day 14 to 21, day 21 to 28, day 28 to 32 weeks’ PMA, and 32 weeks’ PMA to 36 weeks’ PMA did not differ between treatment groups. Independent of treatment group, higher growth rates from day 21 to day 28 were associated with a lower risk of Bayley III cognitive score

Anhedonia-defined as loss of interest or pleasure-is one of two core symptoms of major depressive disorder (MDD). Anhedonia may involve decreased enjoyment of potentially rewarding activities and decreased motivation to engage in such activities. Increased engagement with reinforcers-activities with the potential to be positive experiences-is a frequent target of cognitive-behavioral therapies. Nevertheless, how environmental reinforcers are perceived, and how decisions to approach or avoid them are made by individuals with MDD, is largely unknown. We developed an experimental Behavioral Approach Motivation Paradigm to study how activities are evaluated and approached in MDD. Twenty-one MDD participants and 23 healthy controls performed an experimental task that rated activity words for their hedonic value, then engaged in an approach-avoidance joystick task with each individual's unique set of 'liked' and 'disliked' activity words. A negative correlation was observed between anhedonia and the number of 'liked' activities across participants. No significant difference between approach and avoidance behavior was found in direct comparisons between healthy controls and MDD participants; however, weaker avoidance and greater approach toward 'disliked' activities was found in MDD participants. This suggests negative bias in selecting environmental opportunities, potentially further compromising access to hedonic experiences in MDD.

BackgroundCognitive remediation (CR) training has emerged as a promising approach to improving cognitive deficits in schizophrenia and related psychosis. The limited availability of psychological services for psychosis is a major barrier to accessing this intervention however. This study investigated the effectiveness of a low support, remotely accessible, computerised working memory (WM) training programme in patients with psychosis.MethodsNinety patients were enrolled into a single blind randomised controlled trial of CR. Effectiveness of the intervention was assessed in terms of neuropsychological performance, social and occupational function, and functional MRI 2 weeks post-intervention, with neuropsychological and social function again assessed 3–6 months post-treatment.ResultsPatients who completed the intervention showed significant gains in both neuropsychological function (measured using both untrained WM and episodic task performance, and a measure of performance IQ), and social function at both 2-week follow-up and 3–6-month follow-up timepoints. Furthermore, patients who completed MRI scanning showed improved resting state functional connectivity relative to patients in the placebo condition.ConclusionsCR training has already been shown to improve cognitive and social function in patient with psychosis. This study demonstrates that, at least for some chronic but stable outpatients, a low support treatment was associated with gains that were comparable with those reported for CR delivered entirely on a 1:1 basis. We conclude that CR has potential to be delivered even in services in which psychological supports for patients with psychosis are limited.

Supplemental Digital Content is Available in the Text. Metabolic profiling coupled with extreme sampling identified lysophosphatidylcholines 26:0 and 28:1 to be potential biomarkers for multisite musculoskeletal pain., Musculoskeletal pain often occurs simultaneously at multiple anatomical sites. The aim of the study was to identify metabolic biomarkers for multisite musculoskeletal pain (MSMP) by metabolomics with an extreme phenotype sampling strategy. The study participants (n = 610) were derived from the Newfoundland Osteoarthritis Study. Musculoskeletal pain was assessed using a self-reported pain questionnaire where painful sites were circled on a manikin by participants and the total number of painful sites were calculated. Targeted metabolomic profiling on fasting plasma samples was performed using the Biocrates AbsoluteIDQ p180 kit. Plasma cytokine concentrations including tumor necrosis factor-α, interleukin-6, interleukin-1β, and macrophage migration inhibitory factor were assessed by enzyme-linked immunosorbent assay. Data on blood cholesterol profiles were retrieved from participants' medical records. Demographic, anthropological, and clinical information was self-reported. The number of reported painful sites ranged between 0 and 21. Two hundred and five participants were included in the analysis comprising 83 who had ≥7 painful sites and 122 who had ≤1 painful site. Women and younger people were more likely to have MSMP (P ≤ 0.02). Multisite musculoskeletal pain was associated with a higher risk of having incontinence, worse functional status and longer period of pain, and higher levels of low-density lipoprotein and non–high-density lipoprotein cholesterol (all P ≤ 0.03). Among the 186 metabolites measured, 2 lysophosphatidylcholines, 1 with 26 carbons with no double bond and 1 with 28 carbons with 1 double bond, were significantly and positively associated with MSMP after adjusting for multiple testing with the Bonferroni method (P ≤ 0.0001) and could be considered as novel metabolic markers for MSMP.

OBJECTIVE: To evaluate neurodevelopmental outcomes of preterm infants with need for Child Protective Services (CPS) supervision at hospital discharge compared with those discharged without CPS supervision. STUDY DESIGN: For infants born at

To characterize behavior of 2-year-old children based on the severity of bronchopulmonary dysplasia (BPD).We studied children born at 22-26 weeks of gestation and assessed at 22-26 months of corrected age with the Child Behavior Checklist (CBCL). BPD was classified by the level of respiratory support at 36 weeks of postmenstrual age. CBCL syndrome scales were the primary outcomes. The relationship between BPD grade and behavior was evaluated, adjusting for perinatal confounders. Mediation analysis was performed to evaluate whether cognitive, language, or motor skills mediated the effect of BPD grade on behavior.Of 2310 children, 1208 (52%) had no BPD, 806 (35%) had grade 1 BPD, 177 (8%) had grade 2 BPD, and 119 (5%) had grade 3 BPD. Withdrawn behavior (P .001) and pervasive developmental problems (P .001) increased with worsening BPD grade. Sleep problems (P = .008) and aggressive behavior (P = .023) decreased with worsening BPD grade. Children with grade 3 BPD scored 2 points worse for withdrawn behavior and pervasive developmental problems and 2 points better for externalizing problems, sleep problems, and aggressive behavior than children without BPD. Cognitive, language, and motor skills mediated the effect of BPD grade on the attention problems, emotionally reactive, somatic complaints, and withdrawn CBCL syndrome scales (P values .05).BPD grade was associated with increased risk of withdrawn behavior and pervasive developmental problems but with decreased risk of sleep problems and aggressive behavior. The relationship between BPD and behavior is complex. Cognitive, language, and motor skills mediate the effects of BPD grade on some problem behaviors.

Significance Craniosynostosis (CS) is a frequent congenital malformation featuring premature fusion of cranial sutures; 15% of these children have syndromic disease, often due to rare mutations with large effect. While many genes causing Mendelian forms of syndromic CS have been identified, clinical sequencing often fails to identify a likely causative mutation. We performed whole-exome sequencing of 12 case-parent trios with previously negative genetic evaluations. The results identified likely pathogenic mutations in TFAP2B, KAT6A, GLI2, SOX11, CTNNA1, and GPC4 in these families, adding several loci to those known to cause syndromic CS. The findings have implications for determining risk of disease in subsequent offspring and demonstrate that unexplained syndromic CS cases are a particularly rich vein for discovery of CS loci., Craniosynostosis (CS) is a frequent congenital anomaly featuring the premature fusion of 1 or more sutures of the cranial vault. Syndromic cases, featuring additional congenital anomalies, make up 15% of CS. While many genes underlying syndromic CS have been identified, the cause of many syndromic cases remains unknown. We performed exome sequencing of 12 syndromic CS cases and their parents, in whom previous genetic evaluations were unrevealing. Damaging de novo or transmitted loss of function (LOF) mutations were found in 8 genes that are highly intolerant to LOF mutation (P = 4.0 × 10−8); additionally, a rare damaging mutation in SOX11, which has a lower level of intolerance, was identified. Four probands had rare damaging mutations (2 de novo) in TFAP2B, a transcription factor that orchestrates neural crest cell migration and differentiation; this mutation burden is highly significant (P = 8.2 × 10−12). Three probands had rare damaging mutations in GLI2, SOX11, or GPC4, which function in the Hedgehog, BMP, and Wnt signaling pathways; other genes in these pathways have previously been implicated in syndromic CS. Similarly, damaging de novo mutations were identified in genes encoding the chromatin modifier KAT6A, and CTNNA1, encoding catenin α-1. These findings establish TFAP2B as a CS gene, have implications for assessing risk to subsequent children in these families, and provide evidence implicating other genes in syndromic CS. This high yield indicates the value of performing exome sequencing of syndromic CS patients when sequencing of known disease loci is unrevealing.

Surgery and anesthesia induce inflammatory changes in the central nervous system, which ultimately lead to neuronal damage concomitant with an increase in the level of neurodegeneration markers. Despite some experimental data showing prolonged activation of the immune system post-surgery, no study has determined the extent of long-term elevation of neurodegeneration markers. The purpose of this study was to investigate the serum levels of tau protein, ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1), neurofilament light (NF-L), and glial fibrillary acidic protein (GFAP) after elective cardiac surgery with the implementation of cardiopulmonary bypass (CPB). The serum levels of these markers from 30 patients were compared longitudinally to the baseline (pre-surgery or t0), at 24 hours (t+24), at 7 days (t+7d), and at 3 months (t+3m). The secondary outcome was the production of macrophage-colony stimulating factor (M-CSF) and tumor necrosis factor-α (TNF-α) in vitro by isolated monocytes in response to lipopolysaccharide (LPS) as the measure of immune system activation. The tertiary outcome was the serum level of C-reactive protein (CRP), serum amyloid P (SAP), and α-2-macroglobulin (A2M). Serum levels of tau protein increased 24 hours after surgery (p = 0.0015) and remained elevated at 7 days (p = 0.0017) and three months (p = 0.036). Serum levels of UCH-L1 peaked at 24 hours (p = 0.00055) and normalized at 3 months. In vitro secretion of M-CSF by LPS-stimulated peripheral monocytes, but not TNFα, correlated highly (r = 0.58; p = 0.04) with persistent elevation of serum tau levels at 3 months. The serum CRP and SAP increases correlated with tau post-CPB levels significantly at 3 months. We demonstrated that elevation of serum tau levels at 24 hours, 7 days, and 3 months after heart surgery is concomitant with some traits of inflammation after CPB. The elevation of tau several weeks into recovery is significantly longer than expected.

Growing evidence suggests that the glutamatergic modulator ketamine has rapid antidepressant effects in treatment-resistant depressed subjects. The anticholinergic agent scopolamine has also shown promise as a rapid-acting antidepressant. This study applied genome-wide markers to investigate the role of genetic variants in predicting acute antidepressant response to both agents. The ketamine-treated sample included 157 unrelated European subjects with major depressive disorder (MDD) or bipolar disorder (BD). The scopolamine-treated sample comprised 37 unrelated European subjects diagnosed with either MDD or BD who had a current Major Depressive Episode (MDE), and had failed at least two adequate treatment trials for depression. Change in Montgomery-Asberg Depression Rating Scale (MADRS) or the 17-item Hamilton Depression Rating Scale (HAM-D) scale scores at day 1 (24 h post-treatment) was considered the primary outcome. Here, we conduct pilot genome-wide association study (GWAS) analyses to identify potential markers of ketamine response and dissociative side effects. Polygenic risk score analysis of SNPs ranked by the strength of their association with ketamine response was then calculated in order to assess whether common genetic markers from the ketamine study could predict response to scopolamine. Findings require replication in larger samples in light of low power of analyses of these small samples. Neverthless, these data provide a promising illustration of our future potential to identify genetic variants underlying rapid treatment response in mood disorders and may ultimately guide individual patient treatment selection in the future.

Although total joint replacement (TJR) surgery is considered as the most effective treatment for advanced osteoarthritis (OA) patients, up to one-third of patients reported unfavorable long-term post-operative pain outcomes. We aimed to identify metabolic biomarkers to predict non-responders to TJR using a metabolomics approach. TJR patients were recruited and followed-up at least 1-year post-surgery; TJR outcomes were assessed by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and function subscales. Targeted metabolomic profiling was performed on plasma samples collected pre-surgery and pairwise metabolite ratios, as proxies for enzymatic reactions, were calculated. Association tests were performed between each metabolite ratio and non-responders. The metabolome-wide significance was defined as p < 2 × 10-5 . A total of 461 TJR patients due to primary OA were included in the analysis. Fifteen percent of patients were classified as pain non-responders; 16% were classified as function non-responders. Lower baseline WOMAC pain and function scores were significantly associated with pain and function non-responders, respectively (both p < 0.03). Two metabolite ratios were significantly associated with pain non-responders; acetylcarnitine (C2) to phosphatidylcholine acyl-alkyl C40:1 (PC ae C40:1) was five times higher in pain non-responders whereas phosphatidylcholine diacyl C36:4 (PC aa C36:4) to isoleucine was twenty one times lower in pain non-responders than responders (all p ≤ 1.93 × 10-5 ). One metabolite ratio, glutamine to isoleucine, was significantly lower in function non-responders than responders (eight times lower; p = 1.08 × 10-5 ). Three metabolite ratios (C2 to PC ae C40:1, PC aa C36:4, and glutamine to isoleucine) related to inflammation and muscle breakdown could be considered as novel plasma markers for predicting non-responders to TJR and warrant further investigation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:793-802, 2020.

Objectives: This study aimed to explore changes in verbal comprehension subtest and index scores from Wechsler Intelligence Scale for Children, fourth edition (WISC)-IV to WISC-V for individuals with autism spectrum disorder (ASD), as the test revision dropped the subtest that has proven to be most challenging for those with ASD (i.e. Comprehension). Methods: In all, 48 children with ASD who had been assessed with WISC-IV and re-evaluated with WISC-V were included in this study. Paired samples t-tests were used to examine changes in scores between administrations. Results: Results indicated that changes in subtest scores were minimal although a statistically significant index score change occurred. Discussion: These data suggest that administering additional measures of verbal intellect to individuals with ASD (i.e. beyond the two core verbal comprehension subtests of WISC-V) is critical for capturing the totality of their strengths and weaknesses, to effectively inform treatment planning.

© 2019 Journal of Shoulder and Elbow Surgery Board of Trustees Background: Total elbow arthroplasty (TEA) is a reliable treatment for elderly patients with comminuted intra-articular distal humeral fractures. However, the longevity and long-term complications associated with this procedure are unknown. The objectives of this study were to examine long-term outcomes and implant survival in elderly patients undergoing TEA for fracture. Methods: Patients from a previously published randomized controlled trial of 42 patients in which TEA was compared with open reduction–internal fixation (ORIF) were followed up long term. Patients were aged 65 years or older with comminuted intra-articular distal humeral fractures. Outcomes included patient-reported grading of function and pain, revision surgical procedures, and implant survival. Results: Data were obtained for 40 patients, 15 treated with ORIF and 25 treated with TEA, with a mean follow-up period of 12.5 years for surviving patients and 7.7 years for deceased patients. The reoperation rate was 3 of 25 in the TEA group and 4 of 15 in the ORIF group (P = .39). Of the 25 patients with TEAs, only 1 required (early) revision arthroplasty; 7 were living with their original arthroplasty, and 15 died with a well-functioning implant in situ. Three were lost to follow-up. Conclusions: TEA is an effective and reliable procedure for the treatment of comminuted distal humeral fractures in the elderly patient. Our study reveals reliable implant long-term survival, with no patient requiring a late revision. For the majority of these patients, a well-performed TEA will give them a well-functioning elbow for life and will be the last elbow procedure required.

ObjectiveThe clinical presentation and course of Crohn's disease (CD) is highly variable. We sought to better understand the cellular and molecular mechanisms that guide this heterogeneity, and characterise the cellular processes associated with disease phenotypes.DesignWe examined both gene expression and gene regulation (chromatin accessibility) in non-inflamed colon tissue from a cohort of adult patients with CD and control patients. To support the generality of our findings, we analysed previously published expression data from a large cohort of treatment-naïve paediatric CD and control ileum.ResultsWe found that adult patients with CD clearly segregated into two classes based on colon tissue gene expression—one that largely resembled the normal colon and one where certain genes showed expression patterns normally specific to the ileum. These classes were supported by changes in gene regulatory profiles observed at the level of chromatin accessibility, reflective of a fundamental shift in underlying molecular phenotypes. Furthermore, gene expression from the ilea of a treatment-naïve cohort of paediatric patients with CD could be similarly subdivided into colon-like and ileum-like classes. Finally, expression patterns within these CD subclasses highlight large-scale differences in the immune response and aspects of cellular metabolism, and were associated with multiple clinical phenotypes describing disease behaviour, including rectal disease and need for colectomy.ConclusionsOur results strongly suggest that these molecular signatures define two clinically relevant forms of CD irrespective of tissue sampling location, patient age or treatment status.

The study presents a critical analysis of written expression curriculum-based measurement (WE-CBM) metrics derived from 3- and 10-min test lengths. Criterion validity and classification accuracy were examined for Total Words Written (TWW), Correct Writing Sequences (CWS), Percent Correct Writing Sequences (%CWS), and Correct Minus Incorrect Writing Sequences (CMIWS). Fourth grade students (n = 109) from 6 schools participated in the study. To assess criterion validity of each metric, total scores from writing tasks were correlated with the state achievement test's composition subtest. Each index investigated was moderately correlated with the subtest. Correlations increased with the longer sampling period, however they were not statistically significant. The accuracy at distinguishing between proficient and not proficient writers on the state assessment was analyzed for each index using discriminant function analysis and Receiver Operating Characteristic (ROC) curves. CWS and CMIWS, indices encompassing production and accuracy, were most accurate for predicting proficiency. Improvements were observed in classification accuracy with an increased sampling time. Utilizing cut scores to hold sensitivity above .90, specificity for each metric increased with longer probes. Sensitivity and specificity increased for all metrics with longer probes when using a 25th percentile cut. Visual analyses of ROC curves reveal where classification improvements were made. The 10-min sample for CWS more accurately identified at-risk students in the center of the distribution. Without measurement guiding decisions, writers in the middle of the distribution are more difficult to classify than those who clearly write well or struggle. The findings have implications for screening using WE-CBM. (PsycINFO Database Record

Objective.To compare SMAD3 gene expression between human osteoarthritic and healthy cartilage and to examine whether expression is regulated by the promoter DNA methylation of the gene.Methods.Human cartilage samples were collected from patients undergoing total hip/knee joint replacement surgery due to primary osteoarthritis (OA), and from patients with hip fractures as controls. DNA/RNA was extracted from the cartilage tissues. Real-time quantitative PCR was performed to measure gene expression, and Sequenom EpiTyper was used to assay DNA methylation. Mann-Whitney test was used to compare the methylation and expression levels between OA cases and controls. Spearman rank correlation coefficient was calculated to examine the association between the methylation and gene expression.Results.A total of 58 patients with OA (36 women, 22 men; mean age 64 ± 9 yrs) and 55 controls (43 women, 12 men; mean age 79 ± 10 yrs) were studied. SMAD3 expression was on average 83% higher in OA cartilage than in controls (p = 0.0005). No difference was observed for DNA methylation levels in the SMAD3 promoter region between OA cases and controls. No correlation was found between SMAD3 expression and promoter DNA methylation.Conclusion.Our study demonstrates that SMAD3 is significantly overexpressed in OA. This overexpression cannot be explained by DNA methylation in the promoter region. The results suggest that the transforming growth factor-β/SMAD3 pathway may be overactivated in OA cartilage and has potential in developing targeted therapies for OA.

Background: Central nervous system-derived interleukin-1β plays a role in mood disorders. P2X7 receptor activation by adenosine-triphosphate leads to the release of interleukin-1β. Aims: This first-in-human study evaluated safety, tolerability, pharmacokinetics and pharmacodynamics of a novel central nervous system-penetrant P2X7 receptor antagonist, JNJ-54175446, in healthy participants. Methods: The study had three parts: an ascending-dose study in fasted participants (0.5–300 mg JNJ-54175446); an ascending-dose study in fed participants (50–600 mg); and a cerebrospinal fluid study (300 mg). Target plasma concentrations were based on estimated plasma effective concentration (EC)50 (105 ng/mL) and EC90 (900 ng/mL) values for central nervous system P2X7 receptor binding. Results: Seventy-seven participants received a single oral dose of JNJ-54175446 ( n=59) or placebo ( n=18). Area under the curve of concentration time extrapolated to infinity (AUC∞) increased dose-proportionally; maximum concentration (Cmax) of plasma (Cmax,plasma) increased less than dose-proportionally following single doses of JNJ-54175446. Because food increases bioavailability of JNJ-54175446, higher doses were given with food to evaluate safety at higher exposures. The highest Cmax,plasma reached (600 mg, fed) was 1475±163 ng/mL. JNJ-54175446 Cmax in cerebrospinal fluid, a proxy for brain penetration, was seven times lower than in total plasma; unbound Cmax,plasma and Cmax,CSF were comparable (88.3±35.7 vs 114±39 ng/mL). JNJ-54175446 inhibited lipopolysaccharide/3′-O-(4-benzoylbenzoyl)-ATP-induced interleukin-1β release from peripheral blood in a dose-dependent manner (inhibitory concentration (IC)50:82 ng/mL; 95% confidence interval: 48–94). Thirty-three of 59 (55.9%) participants reported at least one treatment-emergent adverse event; the most common adverse event being headache (11/59, 18.6%). Conclusion: Plasma exposure of JNJ-54175446 was dose-dependent. No serious adverse events occurred. Single-dose administration of JNJ-54175446>10 mg attenuated ex-vivo lipopolysaccharide-induced interleukin-1β release in peripheral blood. Passive brain penetration of JNJ-54175446 was confirmed.

BACKGROUND. Crohn’s disease (CD) is highly heterogeneous, due in large part to variability in cellular processes that underlie the natural history of CD, thereby confounding effective therapy. There is a critical need to advance understanding of the cellular mechanisms that drive CD heterogeneity. METHODS. We performed small RNA sequencing of adult colon tissue from CD and NIBD controls. Colonic epithelial cells and immune cells were isolated from colonic tissues, and microRNA-31 (miR-31) expression was measured. miR-31 expression was measured in colonoid cultures generated from controls and patients with CD. We performed small RNA-sequencing of formalin-fixed paraffin-embedded colon and ileum biopsies from treatment-naive pediatric patients with CD and controls and collected data on disease features and outcomes. RESULTS. Small RNA-sequencing and microRNA profiling in the colon revealed 2 distinct molecular subtypes, each with different clinical associations. Notably, we found that miR-31 expression was a driver of these 2 subtypes and, further, that miR-31 expression was particularly pronounced in epithelial cells. Colonoids revealed that miR-31 expression differences are preserved in this ex vivo system. In adult patients, low colonic miR-31 expression levels at the time of surgery were associated with worse disease outcome as measured by need for an end ileostomy and recurrence of disease in the neoterminal ileum. In pediatric patients, lower miR-31 expression at the time of diagnosis was associated with future development of fibrostenotic ileal CD requiring surgery CONCLUSIONS. These findings represent an important step forward in designing more effective clinical trials and developing personalized CD therapies. FUNDING. This work was supported by CCF Career Development Award (SZS), R01-ES024983 from NIEHS (SZS and TSF), 1R01DK104828-01A1 from NIDDK (SZS and TSF), P01-DK094779-01A1 from NIDDK (SZS), P30-DK034987 from NIDDK (SZS), 1-16-ACE-47 ADA Pathway Award (PS), UNC Nutrition Obesity Research Center Pilot & Feasibility Grant P30DK056350 (PS), CCF PRO-KIIDS NETWORK (SZS and PS), UNC CGIBD T32 Training Grant from NIDDK (JBB), T32 Training Grant (5T32GM007092-42) from NIGMS (MH), and SHARE from the Helmsley Trust (SZS). The UNC Translational Pathology Laboratory is supported, in part, by grants from the National Cancer Institute (3P30CA016086) and the UNC University Cancer Research Fund (UCRF) (PS).

Objective To investigate associations in toddlers born extremely preterm ( Study design Cohort analysis from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network Surfactant Positive Airway Pressure and Pulse Oximetry Trial Neuroimaging and Neurodevelopmental Outcomes Study of infants born extremely preterm. Subjects underwent cranial ultrasonography and near-term magnetic resonance imaging (MRI). At 18-22 months of corrected age, the assessment included the Brief Infant Toddler Social Emotional Assessment (BITSEA) Problem and Competence Scale scores and the Bayley Scales of Infant Development, Third Edition (Bayley-III). The BITSEA Problem Scale assesses dysregulation; the Competence Scale assesses social-emotional competence. We examined associations of Problem and Competence scores and positive screen rates with cranial ultrasonography and near-term MRI. Mean BITSEA and Bayley-III scores were compared using ANOVA and positive screen rates with the χ2 test. We computed correlations between BITSEA and Bayley-III scores. Results Of the 397 children, positive BITSEA screens were found in 34% for the Problem score and 26% for the Competence score. Presence of lesions on near-term MRI that included cerebellar lesions were significantly associated with lower BITSEA Competence but not with Problem scores; Competence scores were inversely related to the presence/significance of lesions. Positive screens on Competence scores and on both Competence and Problem scores were significantly associated with Bayley-III cognitive and language scores Conclusions Social–emotional competence contributes to deficits in cognitive and language development. Presence of injury on near-term MRI that includes cerebellar lesions is associated with later social–emotional competence and may be a useful predictor to guide early assessment and intervention. Trial registration ClinicalTrials.gov : NCT00063063 and NCT00233324 .

Cave roosting bats represent an important component of Southeast Asian bat diversity and are vulnerable to human disturbance during critical reproductive periods (pregnancy, lactation and weaning). Because dramatic growth of cave tourism in recent decades has raised concerns about impacts on cave bats in the region, we assessed the reproductive phenology of two insectivorous species (Hipposideros larvatus sensu lato and Taphozous melanopogon) at three caves in Cambodia for 23 months in 2014–2016 and evaluated human visitation to these sites between 2007 and 2014. Despite the differing foraging strategies employed by the two taxa, the temporal consistency observed in proportions of pregnant, lactating and juvenile bats indicates that their major birth peaks coincide with the time of greatest cave visitation annually, particularly for domestic visitors and namely during the Cambodian new year in April. They also reflect rainfall patterns and correspond with the reproductive phenology of insectivorous cave bats in Vietnam. These findings were predictable because 1) insect biomass and thus food availability for insectivorous bats are optimal for ensuring survival of young following this period, and 2) the Khmer new year is the most significant month for religious ceremonies and thus domestic cave visitation nationally, due to the abundance of Buddhist shrines and temples in Cambodian caves. While the impact of visitor disturbance on bat population recruitment cannot be empirically assessed due to lack of historical data, it is nonetheless likely to have been considerable and raises a conservation concern. Further, because growing evidence suggests that insectivorous cave bats exhibit reproductive synchrony across continental Southeast Asia where countless cave shrines are heavily frequented during April in Theravada Buddhist countries (e.g., Myanmar, Thailand, Cambodia and Laos), our results may have wider applicability in the region. We consequently advocate for increased emphasis on sustainable cave management practices in Cambodia and further investigations to determine whether our findings present a broader concern for cave bat conservation in Southeast Asia.

Importance Studies of cranial ultrasonography and early childhood outcomes among cohorts of extremely preterm neonates have linked periventricular-intraventricular hemorrhage and cystic periventricular leukomalacia with adverse neurodevelopmental outcomes. However, the association between nonhemorrhagic ventriculomegaly and neurodevelopmental and behavioral outcomes is not fully understood. Objective To characterize the outcomes of extremely preterm neonates younger than 27 weeks’ gestational age who experienced nonhemorrhagic ventriculomegaly that was detected prior to 36 weeks’ postmenstrual age. Design, Setting, and Participants This longitudinal observational study was conducted at 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants born prior to 27 weeks’ gestational age in any network facility between July 1, 2006, and June 30, 2011, were included if they had a cranial ultrasonogram performed prior to 36 weeks’ postmenstrual age. Comparisons were made between those with ventriculomegaly and those with normal cranial sonograms. Data analysis was completed from August 2013 to August 2017. Main Outcomes and Measures The main outcome was neurodevelopmental impairment, defined as a Bayley Scales of Infant and Toddler Development III cognitive score less than 70, moderate/severe cerebral palsy, a Gross Motor Function Classification System score of level 2 or more, vision impairment, or hearing impairment. Secondary outcomes included Bayley Scales of Infant and Toddler Development III subscores, components of neurodevelopmental impairment, behavioral outcomes, and death/neurodevelopmental impairment. Logistic regression was used to evaluate the association of ventriculomegaly with adverse outcomes while controlling for potentially confounding variables and center differences as a random effect. Linear regression was used similarly for continuous outcomes. Results Of 4193 neonates with ultrasonography data, 300 had nonhemorrhagic ventriculomegaly (7%); 3045 had normal cranial ultrasonograms (73%), 775 had periventricular-intraventricular hemorrhage (18.5%), and 73 had cystic periventricular leukomalacia (1.7%). Outcomes were available for 3008 of 3345 neonates with ventriculomegaly or normal scans (90%). Compared with normal cranial ultrasonograms, ventriculomegaly was associated with lower gestational age, male sex, and bronchopulmonary dysplasia, late-onset sepsis, meningitis, necrotizing enterocolitis, and stage 3 retinopathy of prematurity. After adjustment, neonates with ventriculomegaly had higher odds of neurodevelopmental impairment (odds ratio [OR], 3.07; 95% CI, 2.13-4.43), cognitive impairment (OR, 3.23; 95% CI, 2.09-4.99), moderate/severe cerebral palsy (OR, 3.68; 95% CI, 2.08-6.51), death/neurodevelopmental impairment (OR, 2.17; 95% CI, 1.62-2.91), but not death alone (OR, 1.09; 95% CI, 0.76-1.57). Behavioral outcomes did not differ. Conclusions and Relevance Nonhemorrhagic ventriculomegaly is associated with increased odds of neurodevelopmental impairment among extremely preterm neonates.

Multiple factors can help predict knee osteoarthritis (OA) patients from healthy individuals, including age, sex, and BMI, and possibly metabolite levels. Using plasma from individuals with primary OA undergoing total knee replacement and healthy volunteers, we measured lysophosphatidylcholine (lysoPC) and phosphatidylcholine (PC) analogues by metabolomics. Populations were stratified on demographic factors and lysoPC and PC analogue signatures were determined by univariate receiver-operator curve (AUC) analysis. Using signatures, multivariate classification modeling was performed using various algorithms to select the most consistent method as measured by AUC differences between resampled training and test sets. Lists of metabolites indicative of OA [AUC > 0.5] were identified for each stratum. The signature from males age > 50 years old encompassed the majority of identified metabolites, suggesting lysoPCs and PCs are dominant indicators of OA in older males. Principal component regression with logistic regression was the most consistent multivariate classification algorithm tested. Using this algorithm, classification of older males had fair power to classify OA patients from healthy individuals. Thus, individual levels of lysoPC and PC analogues may be indicative of individuals with OA in older populations, particularly males. Our metabolite signature modeling method is likely to increase classification power in validation cohorts.

Article first published online 6 July 2015. Supplemental Digital Content is Available in the Text., Background: There is a dire need for reliable prognostic markers that can guide effective therapeutic intervention in Crohn's disease (CD). We examined whether different phenotypes in CD can be classified based on colonic microRNA (miRNA) expression and whether miRNAs have prognostic utility for CD. Methods: High-throughput sequencing of small and total RNA isolated from colon tissue from patients with CD and controls without Inflammatory Bowel Disease (non-IBD) was performed. To identify miRNAs associated with specific phenotypes of CD, patients were stratified according to disease behavior (nonstricturing, nonpenetrating; stricturing; penetrating), and miRNA profiles in each subset were compared with those of the non-IBD group. Validation assays were performed using quantitative reverse transcription polymerase chain reaction. These miRNAs were further evaluated by quantitative reverse transcriptase polymerase chain reaction on formalin-fixed, paraffin-embedded tissue (index biopsies) of patients with nonpenetrating CD at the time of diagnosis that either retained the nonpenetrating phenotype or progressed to penetrating/fistulizing CD. Results: We found a suite of miRNAs, including miR-31-5p, miR-215, miR-223-3p, miR-196b-5p, and miR-203 that stratify patients with CD according to disease behavior independent of the effect of inflammation. Furthermore, we also demonstrated that expression levels of miR-215 in index biopsies of patients with CD might predict the likelihood of progression to penetrating/fistulizing CD. Finally, using a novel statistical simulation approach applied to colonic RNA-sequencing data for patients with CD and non-IBD controls, we identified miR-31-5p and miR-203 as candidate master regulators of gene expression profiles associated with CD. Conclusions: miRNAs may serve as clinically useful prognostic markers guiding initial therapy and identifying patients who would benefit most from effective intervention.

ObjectivesThe initial management of a trauma patient often involves imaging in the form of x-rays, computed tomography (CT) and other radiographic studies, which expose the patient to ionizing radiation, an entity known to cause tissue injury and malignancy at high doses. The purpose of this study was to use a calculation-based method to determine the radiation exposure of trauma patients undergoing trauma team activation in a Canadian tertiary-care trauma centre.MethodsA retrospective chart review was conducted using the Nova Scotia Provincial Trauma Registry. All patients age 16 years old and over who underwent trauma team activation between March 1, 2008 and March 1, 2009 were included. Patients who died prior to imaging tests were excluded. Dose reports for each CT were used to calculate a whole-body radiation dose for each patient.ResultsThere were 230 trauma team activations during the study period, of which 206 had CT imaging. Data were available for 162 patients. The mean whole-body radiation exposure for all patients was 24.4±10.3 mSv, which may correlate to one additional cancer death for every 100 trauma patients scanned.ConclusionsTrauma patients are exposed to significant amounts of radiation during their initial trauma work-up, which may increase the risk of fatal cancer. Clinicians who care for these patients must be aware of the radiation exposure, and take measures to limit radiation exposure of trauma patients.

Radiographic measurements to document ankle anatomy have been suggested in recent literature to be inadequate. Focus has been put on stress views and computed tomography; however, there are also issues with these modalities. An orthogonal view that could be used both statically and dynamically could help determine syndesmotic stability. The purpose of this study was to determine a parameter on a normal lateral ankle radiograph that will increase the reliability of standard radiography in diagnosing syndesmotic integrity.Three orthopedic surgeons reviewed 80 lateral ankle radiographs. Thirty of those radiographs were reviewed on a second occasion. Rotation of the radiographs was determined by evaluating the overlap of the talar dome. Four radiographic parameters were measured 1 cm above the tibial plafond: fibular width, tibial width, and anterior and posterior tibiofibular intervals.Seventy-two radiographs were determined by consensus to be adequate. Means and ratios were documented to determine the relationship of the fibula to the tibia. Interrater reliability ranged from moderate to near-perfect, and the intrarater reliability was documented for each ratio. The anterior tibiofibular ratio was shown to be strong to near-perfect. It demonstrates that 40% of the tibia should be seen anterior to the fibula at 1cm above the tibial plafond.The anterior tibiofibular ratio provides an orthogonal measure for the syndesmosis that, in conjunction with those parameters previously documented, could clinically and economically improve the diagnosis of syndesmotic disruptions.Selon la littérature récente, les mesures radiographiques utilisées pour documenter l’anatomie de la cheville seraient inadéquates. L’accent a été placé sur les clichés de cheville en position de stress et sur la tomodensitométrie, mais ces modalités présentent également des inconvénients. Une vue orthogonale utilisée en position statique et en position dynamique pourrait aider à évaluer la stabilité syndesmotique. Le but de cette étude était de déterminer quel paramètre de la radiographie latérale normale de la cheville accroîtrait la fiabilité de la radiographie standard pour le diagnostic de l’intégrité syndesmotique.Trois chirurgiens orthopédistes ont passé en revue 80 radiographies latérales de la cheville. Trente de ces radiographies ont été interprétées une deuxième fois. La rotation des radiographies a été déterminée par l’évaluation du chevauchement du dôme talien. Quatre paramètres radiographiques ont été mesurés à 1 cm audessus du plafond tibial : la largeur du péroné, la largeur du tibia et les intervalles tibiofibulaires antérieur et postérieur.Soixante-douze radiographies ont consensuellement été jugées adéquates. Les moyennes et les ratios ont été notés pour établir le rapport péroné-tibia. La fiabilité inter-examinateur a varié de modérée à quasi-parfaite et la fiabilité intra-examinateur a été documentée pour chaque ratio. Le ratio tibiofibulaire antérieur s’est révélé être un paramètre solide à quasi-parfait. Il démontre que 40 % du tibia devrait être visible à l’avant du péroné à 1 cm au-dessus du plafond tibial.Le ratio tibiofibulaire antérieur constitue une mesure orthogonale pour la syndesmose qui, en conjonction avec les paramètres précédemment documentés, permettrait d’améliorer le diagnostic des troubles syndesmotiques aux plans clinique et économique.